This invention relates to chiral derivatives of thiourea compounds, particularly of halopyridyl and thiazolyl thiourea compounds useful as potent non-nucleoside inhibitors of viral reverse transcriptase.
Design of potent inhibitors of human immunodeficiency virus (HIV-1) reverse transcriptase (RT) activity, an enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA, has been a focal point in translational AIDS research efforts. Promising inhibitors include nonnucleoside inhibitors (NNI), which bind to a specific allosteric site of HIV-1 RT near the polymerase site and interfere with reverse transcription by altering either the conformation or mobility of RT, thereby leading to noncompetitive inhibition of the enzyme (Kohlstaedt, L. A. et al., Science, 1992, 256, 1783-1790). The inclusion of structural information in the drug design process should lead to more efficient identification of promising RT inhibitors.
A composite binding pocket constructed with the NNI binding site coordinates of multiple, varied RT-NNI structures was generated to facilitate the rational design of RT inhibitors (WO99/47501 published Sep. 23, 1999). This novel composite binding pocket, together with a computer docking procedure and a structure-based semi-empirical score function, provides a guide to predict the energetically favorable position of novel compounds in the NNI binding site of RT. Using this model, we have attempted to design a variety of novel, potent inhibitors of RT for therapeutic use.
The invention described herein recognizes a previously unknown preference for stereospecific isomers of certain NNI, and provides compounds, compositions, and methods comprising such stereospecific NNI.
The invention provides specific, potent stereospecific compounds as inhibitors of reverse transcriptase (RT) activity. The stereoisomers of the invention inhibit replication of retrovirus, such as human immunodeficiency virus (HIV). In one embodiment, the compounds and compositions of the invention are stereospecific, chiral derivatives of non-nucleoside inhibitors (NNI), specifically R-isomers. Preferred compounds are the R-isomers of carbocyclic or heterocyclic thiourea compounds. More preferred compounds include an electron withdrawing group, for example at R1 of the compound shown as Formula I. Exemplary compounds of the invention are shown in the Examples below, and include R-isomers of halopyridyl and thiazolyl thiourea compounds.
The invention additionally provides compositions and methods for inhibiting reverse transcriptase (RT) activity of a retrovirus, such as HIV-I, by contacting the RT binding site of the retrovirus with a compound of the invention. The methods of the invention are useful for inhibiting replication of a retrovirus, such as HIV-1 and include treating a retroviral infection in a subject, such as an HIV-1 infection, by administering a stereospecific chiral compound or composition of the invention, for example, in a pharmaceutical composition.
The compounds of the invention may be combined with carriers and/or agents to enhance delivery to sites of viral infection, such as targeting antibodies, cytokines, or ligands. The compounds may include chemical modifications to enhance entry into cells, or may be encapsulated in various known delivery systems.